YIV-960 (PHY906, KD018) is an oral form of a spray dried aqueous extract of four herbs, which
have been used in the Orient for more than 1800 years for a variety of gastrointestinal
symptoms including diarrhea, nausea, and vomiting. Extensive clinical and pre-clinical
research has been done indicated that YIV-906 may have synergistic anticancer activities as
well as GI toxicity reduction to cancer treatments, including sorafenib. The proposed plan
will investigate the efficacy and mechanisms of YIV-906 as an adjuvant to sorafenib in the
treatment of patients with Hepatitis B(+)-associated advanced hepatocellular carcinoma.
HCC patients with chronic HBV (+) (HBsAg(+) and IgM anti-HBc (-)), and Child-Pugh A status
will be randomized to either the study arm (YIV-906 plus sorafenib) or control arm (placebo
plus sorafenib). Patients will be stratified according to metastatic status
(extrahepatic/vascular invasion vs. none), and their ECOG performance status (0 vs. 1) at
randomization.
- ARM I: Patients receive Placebo + Sorafenib
- ARM II: Patients receive YIV-906+ Sorafenib
Patients in the study arm will be treated orally each 28-day course with YIV-906 (600 mg (3
capsules) BID) + sorafenib (400 mg BID) according to the following schedule: sorafenib BID
daily treatment for 28 days, and YIV-906 BID 4 days on and 3 days off weekly in each course.
All patients will be evaluated and graded for adverse events according to the NCI Common
Terminology for Adverse Events, version 4.0 (CTCAE). The modified Response Evaluation
Criteria in Solid Tumors (mRECIST) will be used to establish disease response or progression.
Patients will be evaluated for PFS, TTP, OS, antitumor response, QoL and safety every two
courses. Biomarkers are mandatory and will be studied prior to drug administration and day 1
of every other cycle. Gut and oral microbiota studies as well as TCM Syndrome Research are
optional.
PK is only optional in China study sites, and limited to the first 15 male and 15 female
patients. Patients will be randomized to either study drug arm or placebo arm (2:1 ratio). PK
studied immediately prior to dose administration and at 1 hour, 2 hours, 4 hours, and 12
hours post-dose administration on Day 1 of Cycles 1.
Inclusion Criteria:
- Male or females ≥ 18 years old with the ability to take oral drugs
- Diagnosis of advanced HCC according to the American Association for the Study of Liver
Diseases (AASLD) Guidelines (Heimbach et al. 2016) or diagnosis by tissue pathology
- Life expectancy of at least 3 months
- Presence of chronic hepatitis B (HBsAg (+), anti-HBc (+), IgM anti-HBc (-) and
anti-HBs(-))
- Never received systemic antitumor therapy
- Patients must have at least one tumor lesion that meets both of the following
criteria:
- "Measurable disease" according to mRECIST, i.e. at least one measurable lesion.
- The lesion has not been previously treated with local therapy
- Patients with an Eastern Cooperative Oncology Group (ECOG) performance status ≤1
- Cirrhotic status of current Child-Pugh class A. Child-Pugh status should be calculated
based on clinical findings and laboratory results during the screening period
- For patients with positive HBV-DNA and/or positive HBsAg results, they must be treated
with antivirals, as prophylaxis starting at least 1-2 weeks prior to receiving study
drug
- Patients with adequate organ reserve, such as laboratory parameters:
- Absolute Neutrophil Count (ANC) ≥ 1.5 x 10^9/L
- Platelets ≥ 60000 x 10^6/L
- Hemoglobin (Hgb) ≥ 9 g/dL
- Serum alanine amino-transferase (ALT) ≤ 5 x ULN
- Adequate renal function, based upon meeting the following laboratory criteria within 7
days before randomization:
- Serum creatinine ≤ 1.5 x ULN or calculated creatinine clearance ≥ 40mL/min (using
the Cockroft-Gault equation: (140-age) x weight (kg)/(serum creatinine x 72
[mg/dL] for males. (For females multiply by 0.85)
- AND
- Urine protein/creatine ratio (UPCR) ≤ 1 mg/mg (≤113.1 mg/mmol) or 24-hour urine
protein <1 g
- Ability to understand and willingness to sign a written informed consent and to be
able to follow the visit schedule
Exclusion Criteria:
- Patients who have received systemic chemo-therapies or immunotherapy or molecular
target therapies
- Patients who have received any local anti-cancer therapy within 4 weeks
- Active bleeding (including gastrointestinal bleeding, encephalopathy, and ascites)
during the last 4 weeks prior to Cycle 1
- Patients with a history of allergy to the known components of YIV-906
- Known history of human immunodeficiency virus (HIV) seropositivity
- Known central nervous system metastasis including brain metastasis and meningeal
carcinomatosis
- Hepatocholangial carcinoma, fibrolamellar cell carcinoma and mixed hepatocellular
carcinoma
- Active malignancy (except for definitively treated melanoma in-situ, basal or squamous
cell carcinoma of the skin, or carcinoma in-situ of the cervix) within the past 5
years
- Any severe and/or uncontrolled medical conditions including:
- Unstable angina pectoris, symptomatic congestive heart failure, myocardial
infarction ≤ 6 months prior to Cycle 1 treatment, serious uncontrolled cardiac
arrhythmia, uncontrolled hypertension
- Previous transient ischemic attack (TIA), cerebral vascular accident (CVA),
symptomatic peripheral vascular disease (PVD) within last 6 months of Cycle 1
treatment
- Congenital long QT syndrome
- Patients with active alcohol intake
- Acute and chronic, active infectious disorders and nonmalignant medical illnesses
that are uncontrolled or whose control may be jeopardized by the complications of
this study therapy, in the opinion of the investigator, except chronic HBV or HCV
- Impairment of gastrointestinal function or who have a gastrointestinal disease
that may significantly alter the absorption of study drugs (e.g., ulcerative
disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome)
- Patients who have had organ transplantation
- Patients receiving chronic treatment with corticosteroids (except for intermittent
topical or local injection or aldosterone) or other immunosuppressive agent
- Patients treated with drugs known to be strong inhibitors or inducers of isoenzyme
CYP3A
- Patients who have undergone major surgery ≤ 2 weeks prior to starting study drug or
who have not recovered from surgery
- Patients who have received an investigational drug or therapy within the last 4 weeks
prior to Cycle 1 treatment.
- Pregnant and/or breastfeeding women
- Men and women of childbearing age and potential, who are not willing to use effective
contraception
- Unwilling or unable to follow protocol requirements or to give informed consent
- An ongoing or recent history of autoimmune, psychiatric disorders and drug abuse
- Uncontrolled hereditary or acquired thrombotic or bleeding disorder
- Bowel obstruction, history or presence of inflammatory enteropathy or extensive
intestinal resection
- Therapeutic dose anticoagulation with warfarin, low molecular-weight heparin, or
similar agents
- Chronic therapy with nonsteroidal anti-inflammatory agents or other antiplatelet
agents. Aspirin at doses up to 100 milligrams/day is permitted
- Patients with an estimated or calculated baseline creatinine clearance of less than 30
mL/min should not be enrolled in this trial
- No patient, however, may enroll in this trial if they are taking phenytoin (Dilantin)
- Patients taking traditional Chinese medicines within 14 days prior to enrollment
